ES2198598T3 - DERIVATIVES OF SULFONILUREA AND ITS USE IN THE CONTROL OF THE ACTIVITY OF INTERLEUQUINA-1. - Google Patents

Abstract

THE INVENTION REFERS TO A FORMULA COMPOUND (I), IN WHICH R 1 AND R 2 ARE SUCH AND AS DEFINED IN THE DESCRIPTION, R 2 BEING AN AROMATIC GROUP, USEFUL FOR THE TREATMENT OF SELECTED STATES FROM THE FORMED GROUP BY: MENINGITIS AND SALPINGITIS, SEPTIC SHOCK, DISMISSED INTRAVASCULAR COAGULATION AND / OR SYNDROME OF RESPIRATORY FAILURE OF THE ADULT, ACUTE OR CHRONIC INFLAMMATION, ARTHRITIS, COLANGITIS, COLITIS, ENCEPHALITIS, ENDOCARDITISTISTISTIS, PATHOMARDITISRITISTISTISTIS, PATHOPHARDITISTISTISTIS, REPRODUCTION , VASCULITIS, ACUTE AND DELAYED HYPERSENSITIVITY, REJECTION OF IMPROVEMENTS AND REACTION OF THE IMPLEMENTATION AGAINST THE GUEST, AUTOIMMUNE DISEASES THAT INCLUDE MELLITUS DIABETES AND MULTIPLE SCLEROSIS, PERIODISTIC DISTROSISMISTOSISTROSISTROSISTROSISTROSISTROSISTROSISTROSISTRIALISTRISISIS, PERIODISTIC DISTRICT, SYMPOSISTRIALISM, PERMITSISM, PERFORMANCE SYSTOSIS, CIRCULARISM, PERFORMANCES THAT PRODUCE IL-1 AS AN AUTOCRINE GROWTH FACTOR, CAQUEXIA, ALZHEIMER'S DISEASE, PERFUSION INJURY, DEPRESSION , ARTEROSCLEROSIS, OSTEOPOROSIS IN MAMMALS, INCLUDING HUMANS.

Description

Sulfonylurea derivatives and their use in control of the activity of interleukin-1.

This invention relates to substituted derivatives of urea useful in the treatment of inflammation in joints, central nervous system, gastrointestinal tract, endocardium, pericardium, lung, eyes, ears, skin and system urogenital More particularly, this invention relates to aryl and heteroaryl substituted sulfonylureas which are useful inhibitors of the processing and release of interleukin-1α and interleukin 1-?

The status of IL-1 as important mediators of inflammation is based on many studies demonstrating this proinflammatory cytokine activity. In vivo , these effects manifest themselves as stimulation of cartilage resorption, induction of leukocyte clustering, acute phase response, and fever production and a shock-like state. Changes mediated by the binding of IL-1 to its receptor include the regulation of adhesion molecules and chemokines; stimulation of metalloprotease synthesis; the increase in the synthesis of cyclooxygenase-2 and phospholipase A2, thus increasing the production of prostaglandin; the induction of nitric oxide synthase, thus increasing the production of nitric oxide and the stimulation of the synthesis of IL-6, resulting in changes in the synthesis of acute phase proteins. Two different forms of IL-1 (IL-1a and IL-1?) Are produced by monocytes and macrophages in response to inflammatory stimuli.

The initial translation product of Human IL-1? Is a 31 kDa polypeptide that is incompetent to bind to IL-1 receptors in target cells To promote your biological activity, you must cleaving proIL-1β first by means of a thiol protease to generate a mature polypeptide species of 17 kDa. This protease, interleukin-1 convertase (ICE), is a member of a new family of cytosolic proteases that require a residue of aspartic acid in subsite P1 of their substrates In contrast to proIL-1β, the 31 kDa proIL-1α is competent to bind to IL-1 receptors; however, this cytokine a 17 kDa species is also processed by a protease other than ICE.

Both forms of IL-1 are synthesized without signal sequences, and as a result, these cytokines accumulate in the cytoplasm of monocytes and macrophages activated by LPS. Therefore, unlike most secreted cytokines that are processed by the traditional cell secretory apparatus that involves the endoplasmic reticulum and the Golgi apparatus, IL-1 must gain access to the extracellular compartment through a new secretory pathway. The mechanistic elements of this route remain unknown. However, recent studies have shown that the synthesis of IL-1? Is not coupled to its secretion. Agents that serve as a stimulus to promote posttranslational processing of IL-1? (Both proteolytic cleavage by ICE and release of the mature 17 kDa species) include ATP, cytolytic T cells and ionophores such as nigericin. Importantly, murine peritoneal macrophages activated by LPS in vivo also require a second stimulus to promote an effective release of mature IL-1β, and ATP was shown to serve this capacity. Therefore, the production of IL-1? Is highly regulated both in vitro and in vivo by requiring separate stimuli to promote post-translational transcription, translation and maturation / release.

Therapeutic approaches that seek to inhibit ICE as a means to regulate the production of IL-1 is They are likely to be limited because ICE inhibitors: 1) do not block the release of proIL-1?, Which could be processed extracellularly by other proteases to generate a biologically active mature cytokine species, and 2) do not reduce the production of IL-1α by monocytes / macrophages activated. Therefore an approach therapeutic that prevents the activation of the processing and post-translational release of IL-1 is likely to provide superior efficacy to that of an ICE inhibitor by block the outsourcing of both cytokine species.

The mammalian cells capable of producing IL-1 includes, but is not limited to, keratinocytes, endothelial cells, mesangial cells, epithelial cells of thymus, dermal fibroblasts, chondrocytes, astrocytes, cells glioma, mononuclear phagocytes, granulocytes, T and B lymphocytes and NK cells

The activities of the Interleukin-1 are many. Subcutaneous injection of IL-1 leads to fever, drowsiness, anorexia, generalized myalgia, arthralgia, headache and, when increasing Exposure, hypotension Marginalization of the neutrophils and maximum extravascular infiltration of leukocytes polymorphonuclear (PMN). IL-1 also stimulates that chondriocytes release matrix metalloproteinases, giving as degradation of the cartilage matrix.

Consequently, the pathological states in the that processing and release inhibitors of IL-1 may be useful as therapeutic agents include, but are not limited to, infectious diseases in which there is active infection anywhere in the body, such as meningitis and salpingitis; complication of infections that include septic shock, disseminated intravascular coagulation and / or syndrome respiratory distress in the adult; acute inflammation or chronic due to deposition of antigen, antibody and / or complement; inflammatory conditions, including arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, injury due to reperfusion and vasculitis. Immune-based diseases that may be sensitive to processing and release inhibitors of IL-1 of the invention include, but without limitation, conditions that involve T cells and / or macrophages such such as acute and delayed hypersensitivity, graft rejection and graft versus host disease; diseases autoimmune, including type 1 diabetes mellitus and sclerosis multiple. Inhibitors of processing and release of IL-1 of the invention may also be useful in the treatment of bone resorption and cartilage, as well as diseases that result in excessive deposition of extracellular matrix. Such diseases include diseases periodental, interstitial pulmonary fibrosis, cirrhosis, sclerosis Systemic and keloid formation. The inhibitors of processing and release of IL-1 from the invention may be useful in the treatment of certain tumors that produce IL-1 as a growth factor autocrine and to prevent cachexia associated with certain tumors. Inhibitors of processing and release of IL-1 of this invention may also be useful in the treatment of neuronal diseases with a component inflammatory, including but not limited to disease Alzheimer's, depression and percussion injury. The inhibitors of processing and release of IL-1 can be also useful for treating cardiovascular diseases in which the grouping of monocytes in the subendothelial space plays a role, such as the development of atherosclerotic plaques.

Summary of the invention

The present invention relates to compounds:

1- (4-Chloro-2,6-diisopropylphenyl) -3- [3- (1-hydroxy-1-methylethyl) benzenesulfonyl] -urea;

1- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) -s- [4- (1-hydroxy-1-methylethyl) furan-2-sulfonyl] urea;

1- (1,2,3,5,6,7-hexahydro-4-aza-s-indacen-8-yl) -3- [4- (1-hydroxy-1-methylethyl) -furan-2-sulfonyl ]urea;

1- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) -3- [4- (1-hydroxy-1-methyl) ethyl] thiophene-2-sulfonyl] urea;

1- (4- [1,3] -dioxolan-2-ylfuran-2-sulfonyl) -3- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) urea;

1- (2,6-diisopropylphenyl) -3- [4- (1-hydroxy-1-methylethyl) furan-2-sulfonyl] urea;

1- (2,6-diisopropylphenyl) -3- [4- (1-hydroxy-1-methylethyl) thiophene-2-sulfonyl] urea;

1- (4-acetylthiophene-2-sulfonyl) -3- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) urea;

1- (1 H -benzimidazol-5-sulfonyl) -3- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) urea;

1- (1,2,3,4,5,6,7-hexahydro-s-indacen-4-yl) -3- [4- (1-hydroxy-1-methylethyl) thiophene-2-sulfonyl] urea;

1- (8-Chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl) -3- [4- (1-hydroxy-1-methylethyl) furan-2-sulfonyl] urea;

1- (4-acetylfuran-2-sulfonyl) -3- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) urea;

1- (8-Fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl) -3- [4- (11-hydroxy-1-methylethyl) furan-2-sulfonyl] urea;

1- (4-fluoro-2,6-diisopropylphenyl) -3- [3- (1-hydroxy-1-methylethyl) benzenesulfonyl] -urea;

1- (6-Fluoro-1 H -benzimidazol-5-sulfonyl) -3- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) urea;

1- (4-Chloro-2,6-diisopropylphenyl) -3- (1 H -indole-6-sulfonyl) urea;

1- (4-Chloro-2,6-diisopropylphenyl) -3- (5-fluoro-1 H -indole-6-sulfonyl) urea;

1- [1,2,3,5,6,7-hexahydro-s-indacen-4-yl) -3- (1 H -indole-6-sulfonyl) urea;

1- (5-Fluoro-1 H -indole-6-sulfonyl) -3- (1,2,3,5,6,7-hexahydro-5-indacen-4-yl) urea;

1- [4-Chloro-2,6-diisopropylphenyl] -3- [2-fluoro-5- (2-methyl- (1,3) -dioxolan-2-yl) benzenesulfonyl] urea;

3- (3- [4-Chloro-2,6-diisopropylphenyl] ureidosulfonyl] - N -methylbenzene-sulfonylamide;

1- [2-Fluoro-5- (2-methyl- (1,3) -dioxolan-2-yl) benzenesulfonyl] -3-1,2,3,5,6,7-hexahydroindacen-4-yl) urea ; Y

3- [3- (1,2,3,5,6,7-hexahydro-S-indacen-4-yl) ureidosulfonyl] - N -methyl-benzenesulfonamide.

The present invention also relates to a pharmaceutical composition for the treatment of meningitis and Salpingitis, septic shock, disseminated intravascular coagulation and / or adult respiratory distress syndrome, inflammation acute or chronic, arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury, vasculitis, acute and delayed hypersensitivity, graft rejection and disease graft versus host, autoimmune diseases including type 1 diabetes mellitus and multiple sclerosis, periodontal diseases, interstitial pulmonary fibrosis, cirrhosis, systemic sclerosis, keloid formation, tumors that produce IL-1 as an autocrine growth factor, cachexia, Alzheimer's disease, percussion injury, depression, atherosclerosis (including cardiomyopathy, myocarditis and heart failure) and osteoporosis in a mammal, including a human being, which comprises administering an amount of a compound of the invention or a pharmaceutically acceptable salt of the same, effective in such treatments or inhibition and a vehicle pharmaceutically acceptable.

The present invention also relates to a procedure to treat a condition selected from the group consisting of meningitis and salpingitis, septic shock, disseminated intravascular coagulation and / or difficulty syndrome respiratory in adults, acute or chronic inflammation, arthritis, cholanrigitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury, vasculitis, hypersensitivity acute and delayed graft rejection and graft disease in front of the host, autoimmune diseases including diabetes Type 1 mellitus and multiple sclerosis, diseases periodontals, interstitial pulmonary fibrosis, cirrhosis, sclerosis systemic, keloid formation, tumors that produce IL-1 as an autocrine growth factor, cachexia, Alzheimer's disease, percussion injury, depression, atherosclerosis (including cardiomyopathy, myocarditis and heart failure) and osteoporosis in a mammal, including a human being, comprising administering to said mammal a amount of a compound of the invention or a salt pharmaceutically acceptable thereof effective in the treatment of such condition

Detailed description of the invention

The following schematic section illustrates the preparation of the present invention, wherein n, A, B, D, E and G in the reaction schemes and the following discussion are defined of so that they provide a compound of the invention.

Preparation A

one

Preparation B

two

Preparation C

3

Preparation D

4

Scheme one

5

In reaction 1 of preparation A, the compound of formula XII becomes the corresponding isocyanate compound of formula XI reacting XII with triphosgene in the presence of a base, such as triethylamine, diisopropylethylamine or 1,8-diazabicyclo [5,4,0] undec-7-eno, and an aprotic solvent, such as tetrahydrofuran, benzene or methylene chloride The mixture is stirred and heated to reflux. over a period of time between about 1 hour at about 3 hours, preferably about 2 hours.

In reaction 1 of preparation B, the compound of formula XIV is converted into the corresponding sulfonamide compound of formula XIII by adding an alkyl lithium, such as n-butyl, sec- butyl or tert- butyl lithium, to a stirred solution of XIV in a polar solvent, such as tetrahydrofuran, at a temperature between about -70 ° C to about -85 ° C, preferably about -78 ° C. After about 15 minutes, liquefied sulfur dioxide is added to the reaction mixture thus formed, stirred at about -78 ° C for 5 minutes and then heated at room temperature for a period of time between about 1 hour to about 3 hours, preferably about 2 hours. The mixture is then (a) concentrated in vacuo and treated with a chlorinating reagent, such as N- chlorosuccinamide in a polar solvent, such as methylene chloride, followed by treatment with aqueous or gaseous ammonia or (b) treated with acid hydroxylamino- O- sulfonic in water in the presence of a buffer, such as sodium acetate.

In reaction 1 of preparation C, the compound of formula XVI becomes the corresponding sulfonamide compound of formula XV by adding a solution of sodium nitrate in water to a stirred solution of XVI in a mixture of acetic acid and hydrochloric acid. Acid is then added acetic acid saturated with gaseous sulfur dioxide followed by chloride cuprous The reaction mixture thus formed is stirred at temperature between about -10 ° C at about 10 ° C, preferably at about 0 ° C, during a period of time between about 1 hour to about 3 hours, preferably about 2 hours. Chloride resulting sulfonyl is then treated with gaseous or aqueous ammonia bubbled through a solution of sulfonyl chloride in a aprotic solvent, such as methylene chloride or ether.

In reaction 1 of preparation D, the compound of formula XVIII becomes the corresponding sulfonamide compound of formula XVII reacting XVIII with chlorosulfonic acid in a polar aprotic solvent, such as chloroform, at a temperature between about -10 ° C to about 10 ° C, preferably at about 0 ° C. The reaction mixture as well formed is heated to approximately 60 ° C. After a period of time from about 1.5 hours to about 2.5 hours, preferably about 2 hours, the reaction mixture is cooled again to a temperature of about 0 ° C and Pour on ice. The resulting sulfonyl chloride is then treated. with gaseous or aqueous ammonia bubbled through a solution of sulfonyl chloride in an aprotic solvent, such as methylene chloride or ether.

In reaction 1 of scheme 1, the compound isocyanate of formula X and the sulfonamide compound of formula IX are convert into the corresponding sulfonylurea compound of the formula VII by reacting IX and X in the presence of a base, such as sodium hydride, sodium hydroxide, triethylamine or 1,8-diazabicyclo [5,4,0] undec-7-eno, and a polar solvent, such as tetrahydrofuran, acetone or dimethylformamide The reaction mixture thus formed is heated to reflux for a period of time between approximately 10 hours at about 14 hours, preferably about 12 hours.

Inhibition of the release of induced IL-1B by ATP

Mononuclear cells are purified from 100 ml of isolated blood using LSM (Organon Teknika). The heparinized blood (1.5 ml of 1000 units / ml of heparin per Apotheconis injection added to each 50 ml syringe) is Dilute with 20 ml of Medium (RMI 1640, 5% FBS, 1% pen./st., 25 mM HEPES, pH 7.3). 30 ml of the diluted blood are placed on 15 ml of LSM (Organons Teknika) in a conical centrifuge tube 50 ml polypropylene. The tubes are centrifuged at 1200 rpm for 30 minutes in Sorvall tabletop centrifuge at temperature environment. Mononuclear cells, located at the interface of plasma and LSM, are removed, diluted with Medium to achieve a final volume of 50 ml and collected by centrifugation as previously. The supernatant is discarded and the cell pellet is Wash 2 times with 50 ml of medium. A sample of 10 µl is taken of the cells suspended before the second wash for counting; based on this count, the washed cells are diluted with medium to a final concentration of 2.0 x 10 6 cells / ml.

0.1 ml of cell suspension is added to each 96-well plate well. Monocytes are allowed to adhere for 2 hours, then non-adherent cells are removed by aspiration and the bound cells are washed twice with 100 µl of Medium. 100 µL of Medium is added to each well, and the cells they are incubated overnight at 37 ° C in an incubator with 5% carbon

The next day, 25 µL of LPS 50 is added ng / ml (in Medium) to each well and the cells are activated for 2 hours at 37 ° C.

The test agents are diluted with dimethylsulfoxide to a final concentration of 10 mM. Starting of this stock solution, the compounds are diluted first 1:50 [5 m of 10 mM mother + 245 m of Chase medium (RPMI 1640, 25 mM Hepes, pH 6.9, 1% FBS, 1% pen./st., LPS 10 ng / ml and 5 mM sodium bicarbonate). A second dilution is prepared adding 10 µL of the test agent 200 µM to 90 µL of Chase medium, providing a final 20 µM concentration of test agent; the concentration of dimethylsulfoxide in this point is 0.2%.

Monocytes activated by LPS are washed once with 100 µl of Chase medium, then 10 µl of medium is added Chase (containing 0.2% dimethylsulfoxide) to each well. I know add 0.011 ml of the 20 µM test agent solutions to the appropriate wells, and monocytes are incubated for 30 minutes at 37 ° C. At this point, 2 mM ATP is introduced by adding 12 µL of a 20 mM stock solution (previously adjusted to pH 7.2 with sodium hydroxide) and the cells are incubated for 3 hours additional at 37 ° C.

96-well plates are centrifuged for 10 minutes at 2000 rpm in a Sorvall tabletop centrifuge for remove cells and cell debris. An aliquot of 90 is removed \ mul of each supernatant and transferred to a bottom plate 96-well round, and this plate is centrifuged a second time to ensure that all cellular waste is removed. 30 are added µL of the resulting supernatant to a well of an ELISA plate IL-1β also containing 70 µl of PBS, 1% of FBS. The ELISA plate is incubated overnight at 4 ° C. The ELISA (R&D Systems) is carried out following the guidelines of the kit

Calculation and analysis of data:

The amount of immunoreactivity IL-1? In Chase medium samples Calculate as follows:

% control = (X-B) / (TOT-B) x 100

wherein X = OD 450 nm of the compound well of testing

B = OD450 of the reagent blank wells in ELISA

TOT = DO450 of the cells that were treated only with 0.2% dimethylsulfoxide.

The compounds of the present invention can be administered in a wide variety of different forms of dosage, in general, therapeutically effective compounds of this invention are present in said dosage forms at  concentration levels in the range of about 5.0% at approximately 70% by weight.

For oral administration, they can be used tablets containing various excipients such as cellulose microcrystalline, sodium citrate, calcium carbonate, phosphate dicalcium and glycine, along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), acid alginic and certain complex silicates, together with binders of granulation such as poly (vinyl pyrrolidone), sucrose, gelatin and gum arabic. Additionally, agents are often very useful lubricants such as magnesium stearate, sodium lauryl sulfate and talc for compression purposes. They can also be used solid compositions of similar type as capsule fillers of jelly; Preferred materials in this regard also include lactose or milk sugar, as well as high polyethylene glycols molecular weight. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient can be combined with various sweetening or flavoring agents, material dye or dyes, and, if desired, emulsifying agents and / or suspension also, together with diluents such as water-ethanol, propylene glycol, glycerin and various Similar combinations thereof.

For parenteral administration (use intramuscular, intraperitoneal, subcutaneous and intravenous), it usually prepares a sterile injectable solution of the active ingredient. Solutions of a compound can be used Therapeutic of the present invention in sesame oil or peanut or in an aqueous propylene glycol. Aqueous solutions they must be properly adjusted and buffered, preferably at a pH greater than 8, if necessary, and become first Isotonic liquid diluent. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions  are suitable for intraarticular, intramuscular injection purposes and subcutaneous. The preparation of all these solutions in Sterile conditions are easily performed using techniques standard pharmaceuticals well known to experts in the technique.

The present invention is illustrated by following examples, but not limited to the details of the same.

Preparation A 3- tert- Butyl sulfamoylbenzenesulfonyl chloride

A solution of 1.46 g (20 mmol) of tert -butylamine and 2.02 g (20 mmol) of triethylamine in tetrahydrofuran was added dropwise to a solution of 5.5 g (20 mmol) of chloride of 1, 3-benzenedisulfonyl in tetrahydrofuran. The reaction was stirred at room temperature for 2 hours. The solvent was evaporated in vacuo. The residue was purified on silica gel, eluting with methylene chloride, to provide 3.86 g of the title compound as an oil.

Preparation B Benzene-1,3-disulfonic acid tert -butylammidomethylamide

5 ml of a 33% solution of methylamine in ethanol was added to a solution of 1.8 g (7 mmol) of 3- tert-butyl sulfamoylbenzenesulfonyl chloride in ethyl acetate. The mixture was stirred for 2 hours. The ethyl acetate phase was separated and concentrated in vacuo. The residue was purified on silica gel eluting with 5% methanol in dichloromethane to provide 1.32 g of the title compound as a white solid.

Preparation C Benzene-1,3-disulfonic acid tert -butylamidodimethylamide

Gaseous dimethylamine was allowed to bubble for 3 minutes in a solution of 1.8 g (7 mmol) of 3- tert- butylsulfamoylbenzenesulfonyl chloride in ethyl acetate. Water was added and the mixture was stirred at room temperature for 1 hour. The ethyl acetate phase was separated, dried over magnesium sulfate and concentrated in vacuo to a solid, which was triturated with hexane: isopropylether, yielding 1.59 g of the title compound. Mp: 100-102 ° C.

Preparation D Benzene-1,3-disulfonic acid amido- tert -butylamide

20 ml of concentrated ammonium hydroxide was added to a solution of 1 g (3.2 mmol) of 3- tert- butylsulfamoylbenzenesulfonyl chloride in ethyl acetate. It was vigorously stirred for 8 hours. The ethyl acetate phase was separated and dried over magnesium sulfate in vacuo to afford 320 mg of the title compound as a white solid. Mp: 151-154 ° C.

Preparation E Benzene-1,3-disulfonic acid tert -butylamidocyclopropylamide

A mixture of 5 ml of cyclopropylamine and 10 ml of water was added to a solution of 1 g (3.9 mmol) of 3- tert- butylsulfamoylbenzenesulfonyl chloride in ethyl acetate. The mixture was stirred at room temperature for 2 hours. The ethyl acetate phase was separated, dried over magnesium sulfate and concentrated in vacuo to an oil, which crystallized with isopropyl ether to provide 839 mg of the title compound as a solid.

Preparation F Benzene-1,3-disulfonic acid tert -butylamidocyclobutylamide

Using a procedure similar to that described in preparation E, 4 ml of cyclobutylamine was added to 1 g (3.9 mmol) of 3- tert-butyl sulfamoylbenzenesulfonyl chloride to provide 813 mg of the title compound.

Preparation G Acid amidomethylamide benzene-1,3-disulfonic

A solution of 1.3 g (4.3 mmol) of benzene-1,3-disulfonic acid tert -butylamidomethylamide in 15 ml of trifluoroacetic acid containing 1 drop of anisole was stirred at room temperature for 12 hours. The trifluoroacetic acid was evaporated in vacuo and the residue was triturated with methylene chloride to provide 330 mg of the title compound. Mp: 124-126 ° C.

The title compounds of the Preparations H-J were prepared by an analogous procedure to that described in Preparation G using the starting material indicated.

Preparation H Acid amidodimethylamide benzene-1,3-disulfonic

Tert -butilamidodimetilamida of benzene-1,3-disulfórnico acid. Mp: 166-167 ° C.

Preparation I Acid amidocyclopropylamide benzene-1,3-disulfonic

Benzene-1,3-disulfonic acid tert -butylamidocyclopropylamide. Mp: 120-121 ° C.

Preparation J Acid amidocyclobutylamide benzene-1,3-disulfonic

Benzene-1,3-disulfonic acid tert -butylamidocyclobutylamide. Mp: 128-130 ° C.

K preparation 3-Methylsulfanylbenzenesulfonamide

A solution of 1.6 M n-butyllithium (12.5 ml, 20 mmol) was added to a solution of m- bromothioanisole (4.06 g, 20 mmol). The solution thus formed was stirred at -78 ° C for 3 hours. Sulfur dioxide was then bubbled to the reaction until it was acidified. The reaction was allowed to warm to room temperature overnight. A solution of N- chlorosuccinimide (2.4 g, 78 mmol) in methylene chloride was added and, after stirring for 1 hour at room temperature, the tetrahydrofuran was evaporated. The residue was suspended in methylene chloride and filtered. The filtrate was mixed with concentrated ammonium hydroxide and stirred at room temperature for 1 hour. The methylene chloride phase was dried and evaporated. The residue was triturated with methylene chloride, providing 1.5 g of the title compound. Mp: 126-127 ° C.

Preparation L 3-Methanesulfonylbenzenesulfonamide

A mixture of 3-methylsulfanylbenzenesulfonamide (406 mg, 2 mmol) and N- chlorosuccinimide (268 mg, 2 mmol) in methanol was stirred at room temperature for 8 hours. Methanol was evaporated and the residue was suspended in methylene chloride and filtered. The filtrate was evaporated to give 250 mg of the title compound as a white solid.

Preparation M 3-Methanesulfonylbenzenesulfonamide

An aqueous solution of OXONE® (3.2 g, 5 was added mmol) to a solution of 3-Methylsulfanylbenzenesulfonamide (500 mg, 2.5 mmol) in acetone The mixture was stirred at room temperature for 12 hours. The reaction was evaporated to dryness in vacuo. The residue is triturated with acetone and filtered. The filtrate was evaporated. providing 460 mg of the title compound.

Preparation N 1- (3-Bromophenyl) cyclobutanol

A 1.6 M solution of n-butyllithium (6.3 ml, 10 mmol) in hexane at a 1,3-dibromobenzene solution (2.36 g, 10 mmol) in tetrahydrofuran at -78 ° C and stirred for 4 hours. Cyclobutanone (700 mg, 10 mmol) was then added in one portion. After stirring for 2 hours at -78 ° C, the reaction was quenched with 2 N hydrochloric acid. The reaction was heated to room temperature, diluted with water and extracted with ethyl acetate. The ethyl acetate phase was dried and evaporated, providing 2.5 g of the crude product, which was purified on gel silica eluting with 50% methylene chloride in hexanes, providing 1.5 g of the title compound.

Preparation O 3- (1-Hydroxycyclobutyl) benzenesulfonamide

A 1.6 M solution of n-butyllithium (8 ml, 12.8 mmol) in hexanes at a 1- (3-bromophenyl) cyclobutanol solution (1.44 g, 6.4 mmol) in tetrahydrofuran at -78 ° C. After 30 minutes, the reaction was allowed to warm to 0 ° C. I know bubbled sulfur dioxide into the reaction mixture and stirred for an additional 30 minutes. The tetrahydrofuran was evaporated and added an aqueous solution of sodium acetate (4.1 g, 50 mmol) and hydroxylaminosulfonic acid (1.85 g, 16 mmol). After stirring to room temperature for 2 hours, the reaction was acidified with 2N hydrochloric acid, then extracted with ethyl acetate. The ethyl acetate was then dried over sodium sulfate and evaporated. The residue was purified on silica gel with dichloromethane: ether providing 70 mg of the compound of Title.

Preparation P 1- (3-Bromophenyl) cyclopentanol

Using a procedure similar to that of the Preparation N, from 2.36 g of 1,3-dibromobenzene, 6.3 ml of 1.6M n-butyl lithium and 840 mg cyclopentanone, se obtained 1.56 g of 1- (3-bromophenyl) cyclopentanol in the form of a oil.

Q preparation 3- (1-Hydroxycyclopentyl) -6-benzenesulfonamide

Using a procedure similar to that of the Preparation O, from 1.5 g of 1- (3-bromophenyl) cyclopentanol, 7.9 ml of 1.6M n-butyl lithium, 1.85 g of acid hydroxylamino-O-sulfonic acid and 4.1 g of NaOAc, 220 mg of 3- (1-hydroxycyclopentyl) benzenesulfonamide in form of a white solid from dichloromethane. P.f .: 146-148 ° C.

R Preparation 1- (3-Bromophenyl) cyclohexanol

Using a procedure similar to that of the Preparation N, from 20 mg (85 mmol) of 1,3-dibromobenzene, 53 ml of n-butyl 1.6 M lithium and 8.3 g of cyclohexanone, 4.9 g of 1- (3-bromophenyl) cyclohexanol in the form of a white solid

Preparation S 3- (1-Hydroxycyclohexyl) benzenesulfonamide

A solution of 1.6M n-butyllithium (12.36 ml, 19.8 mmol) was added to a solution of 1- (3-bromophenyl) cyclohexanol (2.4 g, 9.4 mml) in tetrahydrofuran at -78 ° C. The reaction was stirred for 1 hour, then sulfur dioxide was bubbled into the solution to acidity according to wet pH paper. The reaction was allowed to warm to room temperature for 12 hours. N- Chlorosuccinimide (1.38 g, 10.3 mmol) dissolved in dichloromethane was added and the reaction was stirred for 2 hours. The tetrahydrofuran was evaporated, and the residue was suspended in methylene chloride and filtered. The filtrate was evaporated to 2.1 g of 3- (1-hydroxycyclohexyl) benzenesulfonyl chloride as a brown oil. This was dissolved in methylene chloride and added dropwise to 20 ml of liquid ammonia. The ammonia was allowed to evaporate and the residue was purified on silica gel with dichloromethane / methanol to provide 250 mg of the title compound as a white solid.

The title compounds of the Preparations T-V were prepared by an analogous procedure to that described in Preparation K, using the starting material indicated.

T preparation 3- (2-Methyl- [1,3] -dioxolan-2-yl) benzenesulfonamide

2- (3-Bromophenyl) -2-methyl- [1,3] -dioxolane. Mp .: 96-98 ° C.

U Preparation 3- [1,3] -Dioxolan-2-ylbenzenesulfonamide

2- (3-Bromophenyl) - [1,3] -dioxolane. Mp .: 55-58 ° C.

Preparation V 2-Fluoro-5- (2-methyl- [1,3] -dioxolan-2-yl) benzenesulfonamide

2- [3-Bromo-4-fluorophenyl] -2-methyl- [1,3] -dioxolane. Mp .: 149-150 ° C.

W preparation [2- [4-Bromo-2-nitrophenyl] vinyl] dimethylamine

A solution of 27 g (0.125 mol) of 4-bromo-1-methyl-2-nitrobenzene and 1 ml (0.31 mol of dimethylacetal of N , N- dimethylformamide in 120 ml of DMF was heated at 80 ° C. for 2 hours. After cooling, the reaction was poured into water and extracted with ethyl acetate, then dried over sodium sulfate and evaporated to provide 36 g of the title compound as a purple solid.

Preparation X [2- (4-Bromo-2-nitrophenyl) ethylidene hydrazide of acetic acid

A solution of 36 g of was cooled to 0 ° C [2- [4-Bromo-2-nitrophenyl) vinyl] dimethylamine crude in 75 ml of dimethylformamide. A solution of 26 g was added of semicarbazide hydrochloride in 200 ml of water. They were added then 20 ml of concentrated hydrochloric acid. The solution resulting was then allowed to warm to room temperature. I know filtered a tan precipitate, washed with water and dry.

Preparation Y 6-Bromo-1H-indole

A solution of 375 g of sulfate was added iron (II) heptahydrate in 700 ml of water to a suspension of 35 g of [2- (4-Bromo-2-nitrophenyl) ethylidene hydrazide of the crude acetic acid in 300 ml of ammonium hydroxide concentrated. The mechanically stirred mixture was heated to reflux. for 4 hours, then cooled and filtered. The precipitate is triturated several times with hot ethyl acetate. The phases of Combined ethyl acetate was dried and evaporated, providing 18 g of the title compound.

Z Preparation 1 H -indole-6-sulfonic acid amide

A solution of 6.0 g (0.03 mol) of 6-bromo-1H} -indole was added dropwise to a suspension of 4.5 g (0.03 mol) of 35% KH in mineral oil in ether at 0 ° C. After stirring for 1 hour, the light yellow solution was cooled to -78 ° C. 36.5 ml (0.06 mol) of a 1.7 M solution of tert- butyl lithium in pentane was added dropwise. After stirring for 1 hour at -78 ° C, SO 2 (g) was bubbled into the solution for 5 minutes. The reaction was allowed to cool to room temperature overnight. A solution of 4.1 g (0.03 mol) of N- chlorosuccinimide was added in one portion. After cooling for 1 hour, the reaction was filtered to remove the succinimide and the filtrate was evaporated to a yellow solid. This was dissolved in tetrahydrofuran and added to 20 ml of liquid ammonia. The reaction was allowed to warm to room temperature. The residue was dissolved in ethyl acetate, washed with water, dried and evaporated, yielding 1.4 g of the title compound.

AA Preparation 5-Fluoro-2,3-dihydro-1H-indole

A solution of 6.8 g (0.05 mol) of 5-fluoro-1 H -indole in 50 ml of ether was cooled to 0 ° C under a nitrogen atmosphere. 507 ml of a 0.15 M solution of zinc borohydride in ether was added dropwise. The reaction was allowed to stir for 48 hours. The reaction was quenched with dilute hydrochloric acid. The pH was adjusted to 8.0 with dilute sodium hydroxide. The ether phase was separated, dried and evaporated, yielding 7 g of the title compound.

BB Preparation 1- (5-Fluoro-2,3-dihydroindolyl) ethanone

Acetyl chloride (3 ml) was added dropwise to a solution of 7 g of crude 5-fluoro-2,3-dihydro-1 H -indole and 3 ml of triethylamine in 100 ml of CH2Cl2 } at 0 ° C. After 2 hours, the reaction was diluted with water. The methylene chloride phase was separated, dried and evaporated, yielding 7.3 g of crude product, which was purified on silica gel eluting with hexane / ethyl acetate, providing 3.3 g of the title compound.

CC Preparation Acid amide 1-acetyl-5-fluoro-2,3-dihydro-1H-indole-6-sulfonic

Chlorosulfonic acid (35 ml) was cooled to 0 ° C in nitrogen atmosphere 0.3 g (0.016 were added portionwise moles) of 1- (5-Fluoro-2,3-dihydroindolyl) ethanone. The reaction was heated at 50 ° C for 3 hours, cooled and poured on ice. The resulting white precipitate was filtered and dissolved in methylene chloride. A hydroxide solution was added of concentrated ammonium and the mixture was stirred at room temperature for 1 hour. Volatile compounds were evaporated in vacuo and added dilute hydrochloric acid. The precipitate was filtered and wash with water, providing 3.6 g of the title compound.

DD Preparation Acid amide 5-fluoro-2,3-dihydro-1H-indole-6-sulfonic

A mixture of 3.6 g of 1-acetyl-5-fluoro-2,3-dihydro-1 H -indole-6-sulfonic acid and 30 ml of 2 N sodium hydroxide was heated at 100 ° C for 3 hours. The reaction was cooled and the pH adjusted to 7.0 with acetic acid. The resulting precipitate was filtered, yielding 3.0 g of the title compound.

EE Preparation Acid amide 5-fluoro-1H-indole-6-sulfonic

A mixture of 3 g of manganese dioxide and 3 g of 5-fluoro-2,3-dihydro-1 H -indole-6-sulfonic acid amide in 30 ml of dioxane was heated at 50 ° C overnight. The reaction was filtered and the filtrate was evaporated, yielding a crude product that was purified on silica gel eluting with methylene chloride / ethyl acetate, providing 1.1 g of the title compound. Mp: 181-182 ° C.

FF Preparation 2- (3-Bromophenyl) propan-2-ol

A solution of 3-Bromoacetophenone (29.8 g) in 75 ml of diethyl ether a a stirred solution of methylmagnesium bromide (60 ml of solution 3.0 M in diethyl ether) at 0 ° C. Once the addition is complete, the mixture It was stirred for 0.5 hours and poured into water. The aqueous phase is acidified with 1 M hydrochloric acid and extracted with three portions diethyl ether The combined ether phases were washed with bicarbonate. of saturated sodium and concentrated, providing 30.4 g of title compound. 1 H-NMR δ 7.72 (s a, 1), 7.49 (d, 1 J = 7.8), 7.37 (d, 1, J = 7.9), 7.25 (dd, 1, J = 7.8,  7.9), 4.19 (s, 1), 1.50 (s a, 6).

GG Preparation 2- (3-Aminosulfonylphenyl) propan-2-ol

Methylbutyl lithium (110 ml of a 1.4 M solution in diethyl ether) was added to a stirred solution of 2- (3-bromophenyl) propan-2-ol (30 g) in tetrahydrofuran (1.5 L) at -78 ° C. The solution was stirred at -78 ° C for 15 minutes, then butyllithium (61 ml of a 2.5 M solution in hexane) was added. The solution was stirred for 15 minutes at -78 ° C, at which point a suspension formed. To this suspension was added liquefied sulfur dioxide (approximately 5 equivalents) in one portion. The suspension was stirred at -78 ° C for 5 minutes, then heated to room temperature and stirred for an additional 2 hours. The mixture was concentrated in vacuo to provide a yellow solid that was suspended in water (418 ml). Sodium acetate (190 g) and hydroxylamino- O- sulfonic acid (47.3 g) were added to the aqueous solution, and the solution was stirred overnight. The mixture was extracted with ethyl acetate and the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash chromatography (ethyl acetate / hexane 2: 1) provided 27 g of the title compound. Mp: 107.2-108.2 ° C.

HH Preparation 4-Chloro-2,6-diisopropylaniline

N- Chlorosuccinimide (37.3 g) was added to a stirred solution of 2,6-diisopropylaniline (47 g) in N , N- dimethylformamide (886 ml), and the mixture was stirred overnight. The resulting dark red solution was poured into water (12 ml) and extracted with diethyl ether. The combined ether extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting dark red oil was purified by filtration through silica gel, eluting with hexane: 6: 1 methylene chloride, to provide 32 g of the title compound. 1 H-NMR, δ 7.02 (s, 2), 3.71 (sa, 2), 2.91 (cc, 2, J = 6.9 Hz), 1.27 (d, 6, J = 6.9 Hz), 1.27 (d, 6, J = 6.9 Hz).

Preparation II 4-Chloro-2,6-diisopropylphenyl isocyanate

Triphosgene (14.9 g) was added to a solution hectic of 4-chloro-2,6-diisopropylaniline (32 g) and triethylamine (7.8 ml) in tetrahydrofuran (505 ml). The The mixture was heated at reflux for 2 hours with stirring. He retired then the tetrahydrofuran in vacuo and the resulting oil is suspended in pentane and filtered through silica gel, providing 33.3 g of the product. 1 H-NMR, δ 7.18 (s, 2), 3.22 (cc, 2, J = 7.1 Hz), 1.25 (d, 6, J = 7.1 Hz), 1.25 (d, 6, J = 7.1 Hz).

JJ Preparation 2- [3 - [[[(4-Chloro-2,6-diisopropylphenylamino) amino) carbonyl] amino] sulfonyl] phenyl] -propan-2-ol

Sodium hydride (5.2 g of one 60% dispersion in mineral oil) in several portions at a stirred solution of 2- (3-aminosulfonylphenyl) -propan-2-ol  (26.5 g) in tetrahydrofuran. Once the detachment of hydrogen was added 4-chloro-2,6-diisopropylphenyl isocyanate (30.8 g) in one portion, and the resulting mixture was heated to reflux for 12 hours. The mixture was then cooled to temperature. ambient and concentrated in vacuo. The resulting foam dissolved in water, it was made alkaline with 1 N sodium hydroxide and extracted with two portions of ether / hexane 1: 1. The aqueous phase was acidified with 1 N hydrochloric acid, and the resulting white solid was filtered, washed with water and dried. This provided 50 g of a white solid. which was recrystallized with ethyl acetate / hot hexane providing the title compound, melting point 160.5-162.0 ° C.

KK preparation 5-nitroisophthaloyl chloride

Oxalyl chloride (12.3 ml) and N , N- dimethylformamide (1 drop) were added to a stirred solution of 5-nitroisophthalic acid (10 g) in methylene chloride (943 ml). The reaction mixture was stirred at room temperature overnight. Solvent removal in vacuo provided 10.63 g of the title compound. 1 H-NMR δ 9.17 (s, 2), 9.07 (s, 1).

LL Preparation 3,5-Diacetylnitrobenzene

Magnesium chips (2.27 g) were stirred with ethanol (12 ml) and carbon tetrachloride (1 drop). Once hydrogen evolution completed, malonate was added diethyl (15.18 g) in diethyl ether (30 ml) and the mixture was heated to reflux until all magnesium was consumed. Chloride was added 5-nitroisophthaloyl (10 g) in tetrahydrofuran (29 ml) to the mixture and reflux was continued for 16 hours additional. The mixture was cooled in an ice bath and acidified. with 10% sulfuric acid. The aqueous phase was extracted with acetate. of ethyl and the organic phase was concentrated in vacuo. The oily residue it was suspended in acetic acid (72 ml) and water (14 ml) and added sulfuric acid (4 ml). The mixture was vigorously heated to reflux for 12 hours, then cooled in an ice bath. The mixture was neutralized with 3M sodium hydroxide and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuo to provide 7.54 g of the compound of Title. 1 H-NMR δ 8.90 (s, 2), 8.86 (s, 1H), 2.78 (s, 6)

MM Preparation 3,5-Diacetylaniline

Was added 3,5-diacetylnitrobenzene (7.54 g) to a solution Agitated tin (II) chloride dihydrate (32.87 g) in acid concentrated hydrochloric (93 ml) at 50 ° C. He immediately withdrew heat and an exotherm occurred. The mixture was stirred for 5 minutes, it was cooled in an ice bath and neutralized with a saturated potassium carbonate solution. The aqueous phase is extracted with various portions of ethyl acetate, dried over anhydrous sodium sulfate and concentrated in vacuo to provide 3.01 g of the title compound. 1 H-NMR δ 7.77 (s, 1H), 7.48 (s, 2H), 5.16 (s at, 2H), 2.55 (s, 6).

NN Preparation 3,5-Diacetylbenzenesulfonamide

A solution of sodium nitrate (1.27 was added g) in 2.1 ml of water to a stirred solution of 3,5-diacetylaniline (3.00 g) in an acid mixture acetic acid (17 ml) and hydrochloric acid (5.7 ml). The solution was stirred. during 20 minutes. 14 ml of acetic acid were saturated with dioxide of gaseous sulfur, and this mixture was added to the reaction followed by cuprous chloride (0.63 g). There was a significant formation of foam. The reaction mixture was stirred for one hour, diluted with water and extracted with three portions of ethyl acetate. The Combined ethyl acetate extracts were washed with water and concentrated. The resulting oil was filtered and the solid was suspended in acetone and filtered to remove ammonium chloride. Removal of the acetone in vacuo provided 1.48 g of the compound. of the title. Mp .: 179.2-180.7 ° C.

OO Preparation 1- [3 - [[[(4-Chloro-2,6-diisopropylphenylamino) carbonyl] amino] sulfonyl] -5-acetylphenyl] -ethan-1-one

The title compound was prepared as described in procedure A from 3,5-diacetylbenzenesulfonamide (0.35 g), 4-chloro-2,6-diisopropylphenyl isocyanate (0.37 g), sodium hydride (0.06 g of a 60% dispersion in mineral oil) in tetrahydrofuran (4 ml). This provided 0.28 g. of the title compound. Mp .: 201.9-203.4 ° C.

PP preparation 3-Chloro-1-indan-5-ilpropan-1-one

Aluminum chloride (376 g) was added to a stirred solution of indane (300 g) and chloropropionoyl chloride (323 g) in methylene chloride (2 L) at 0 ° C for a period of 3 hours. Once the addition was completed, the bath was removed from cooling and the mixture was heated to room temperature and stirred until the evolution of hydrogen chloride ceased. The reaction was quenched by pouring it into a mixture of 3.5 kg of ice and 700 ml concentrated hydrochloric acid. The phases separated and the aqueous phase was extracted with methylene chloride. The combined phases of methylene chloride were washed with water, saturated solution of baking soda and brine. The organic phase was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue is recrystallized with hexane, providing 282 g of a solid yellow. Mp .: 63.5-65.1 ° C.

QQ Preparation 3,5,6,7-Tetrahydro-2H-s-indacen-1-one

Concentrated sulfuric acid was added dropwise (550 ml) with stirring for a period of 2 hours at 137 g of 3-chloro-1-indan-5-ilpropan-1-one. The resulting dense black solution was heated at 90 ° C until it ceased. the evolution of hydrogen chloride (usually 1-4 hours) The mixture was then cooled to room temperature and poured into 5 kg of ice. The suspension The resulting was stirred overnight and filtered. The solid was washed  with water until water ran hard through the filter. The tan solid was then dried under vacuum and recrystallized with hexane, providing 90 g of the compound of Title. Mp .: 72.4-74.8 ° C.

RR Preparation 1,2,3,5,6,7-Hexahydro-s-indacene

A mixture of 3,5,6,7-tetrahydro-2 H -s-indacen-1-one (90 g), ethanol (1 L), 10% palladium on carbon (1-2 g) and acid is hydrogen. concentrated hydrochloric (50 ml) in a stirrer For room temperature until hydrogen uptake ceased. The mixture was filtered through a layer of Celite. The layer was washed with 1 L of diethyl ether. The filtrate was diluted with water and the organic phase separated. The aqueous phase was extracted with 1 L of ether, and the combined ether extracts were washed with water, saturated sodium bicarbonate solution and brine. The ether extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting pale yellow solid was recrystallized with methanol, providing 61 g of the title compound as colorless crystals. Mp: 56.6-58.5 ° C.

SS Preparation 1- (1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) ethanone

30 g of aluminum chloride were added to a stirred solution of 1,2,3,5,6,7-hexahydro-s-indacene (30 g) and acetyl chloride (14.2 ml) in 120 ml of benzene at 0 ° C over a period of 1 hour. The cooling bath was removed and the solution was heated to room temperature and stirred for 4 hours. The dark red mixture was then poured into a mixture of 270 g of ice and 50 ml of concentrated hydrochloric acid. The phases are they separated and the aqueous phase was extracted with diethyl ether. Phases combined organics were washed with a saturated solution of baking soda and brine, dried over sodium sulfate anhydrous and concentrated in vacuo to provide an orange solid which was recrystallized with hexane, providing 34 g of the compound of the title. Mp .: 69.1-76.1 ° C.

TT Preparation Rust 1- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) ethanone

It was heated to reflux for a period of 12 hours a mixture of 1- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) ethanone (33 g), ethanol (250 ml), hydroxylamine hydrochloride (58.5 g) and pyridine (80 ml). The mixture was then cooled to room temperature. and concentrated in vacuo. The residue was then treated with 500 ml of water and extracted with chloroform-methanol. The phase The organic was dried over anhydrous sodium sulfate and concentrated to empty, providing 32 g of the title compound as a mixture of E and Z isomers, 178.6-182.3 ° C.

UU Preparation N - (1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) acetamide

A mixture of oxime of 1- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) ethanone (85 g) in 270 ml of trifluoroacetic acid to a stirred solution at 90 ml reflux of trifluoroacetic acid for a period of ½ time. The resulting purple solution was then heated to reflux. for 1 hour. The solution was cooled to room temperature and the Trifluoroacetic acid was removed in vacuo. The dark solid is triturated with ethyl acetate / hexanes, providing 83 g of a gray solid, which was used without further purification. P.f .: 257.4-259.1 ° C.

VV Preparation 1,2,3,5,6,7-Hexahydro-s-indacen-4-ylamine

A suspension of N - (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) acetamide (110 g) in YY ml of 25% sulfuric acid was treated with sufficient ethanol to prepare a solution (approximately YY ml). The resulting solution was heated at reflux for a period of 2 days. The resulting black solution was treated with reflux carbon, filtered hot and cooled to 0 ° C. The solution was then carefully neutralized with a 20% sodium hydroxide solution. The resulting suspension was then filtered and washed with water until the filtrate was neutral. The tan solid was then isolated and dried in vacuo to provide 80 g of the title compound. Mp: 94.5-96.6 ° C, which was used without further purification. If necessary, the title compound can be recrystallized with methanol to provide a white solid.

WW Preparation 1,2,3,5,6,7-Hexahydro-s-indacene

Triphosgene (43.9 g) was added in one portion to a stirred solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-ylamine (77 g) in tetrahydrofuran (1.5 L) and triethylamine (68.3 ml). The mixture was refluxed for D hours, then cooled to room temperature. Tetrahydrofuran was removed under pressure reduced, and the residue was suspended in pentane and filtered through of a silica gel pad. The removal of the pentane to vacuum provided 80 g of a white solid, m.p .: 35.0-36.2 ° C.

XX Preparation 3- (1-Hydroxy-1-methyl) ethylfuran

4.82 ml of 3-furoate was added of ethyl in diethyl ether to a stirred solution of 24.97 ml of methylmagnesium bromide (3M solution in diethyl ether) at 0 ° C. The mixture was gently heated using a hot water bath for 30 minutes After completion, the mixture was poured into ice water, was acidified carefully using a solution buffered and extracted with diethyl ether. The ether extracts are combined, washed with brine, dried over sulfate sodium and concentrated in vacuo. Tertiary alcohol furan is purified using flash column chromatography with hexane / ethyl acetate 6: 1. Recovery: 2.89 g (64%). 1 H-NMR (400 MHz, acetone-d 6) δ 1.45 (s, 3H), 1.46 (s, 3H), 3.89 (s a, 1H), 6.45 (s a, 1H), 7.41 (s a, 1H), 7.42 (s a, 1 HOUR).

YY Preparation 2-Aminosulfonyl-3- (1-hydroxy-1-methyl) ethylfuran

17.19 ml of methyl lithium (solution was added 1.4 M in diethyl ether) to a stirred mixture of 2.89 mg of alcohol tertiary furan in THF at -78 ° C, followed 5 minutes after 18.51 ml of sec} -butyllithium (solution 1.3 M in cyclohexanes). The mixture continued to stir at -78 ° C for 40 minutes, and 5.02 ml of  SO2 liquid. The temperature was maintained at -78 ° C for 5 minutes, and then heated to room temperature and He continued stirring for 2 hours. THF was then removed in vacuo and the lithium sulfate was dissolved in 76.4 ml of water, followed by the addition of 7.78 g of acid hydroxylamino-O} -sulfonic and 31 g of sodium acetate This mixture was stirred at room temperature. overnight and extracted with ethyl acetate. Extracts of ethyl acetate were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The sulfonamide was purified using column chromatography ultrafast with hexane / ethyl acetate 2: 1. Recovery: 1.91 g (41%). Mp .: 110.1-111.6 ° C.

ZZ Preparation 3- (1-Hydroxy-1-methyl) ethylthiophene

1 g of 3-acetylthiophene was added in diethyl ether to a stirred solution of 3.17 ml of bromide methylmagnesium (3M solution in diethyl ether) at 0 ° C. The mixture is allowed to stir after 30 minutes heating at temperature environment. After completion, the mixture was poured into water with ice, acidified and extracted with diethyl ether. The extracts of ether were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. Recovery: 800 mg (71%). 1 H-NMR (400 MHz, acetone-d 6) δ 1.50 (s, 6H), 4.00 (s a, 1H), 7.15 (dd, 1H, J = 1.4, 5), 7.23 (m, 1H), 7.33 (dd, 1H, J = 3.1, 5).

AAA Preparation 2-Aminosulfonyl-3- (1-hydroxy-1-methyl) ethylthiophene

4.22 ml of methyl lithium (1.4 M solution in diethyl ether) was added to a stirred mixture of 800 mg of thiophene tertiary alcohol in THF at -78 ° C, followed 5 minutes after 4.55 ml of sec- butyl lithium ( 1.3 M solution in cyclohexanes). The mixture continued to stir at -78 ° C for 40 minutes and 1.23 ml of liquid SO2 was added. The temperature was maintained at -78 ° C for 5 minutes and then heated to room temperature with continuous stirring for 2 hours. THF was then removed in vacuo and lithium sulphinate was dissolved in 19 ml of water followed by the addition of 1.9 g of hydroxylamino- O- sulfonic acid and 7.66 g of sodium acetate. This mixture was stirred at room temperature overnight and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. Sulfonamide was purified using flash column chromatography with hexane / ethyl acetate 2: 1. Recovery: 600 mg (48%), mp: 114.3-115.1 ° C.

Example 1 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3- (1-hydroxy-1-methylethyl) benzenesulfonyl] urea

Sodium hydride (5.2 g of one 60% dispersion in mineral oil) in several portions at a stirred solution of 2- (3-aminosulfonylphenyl) propan-2-ol (26.5 g) in tetrahydrofuran. Once the detachment of hydrogen was added 4-chloro-2,6-diisopropylphenyl isocyanate (30.8 g) in one portion, and the resulting mixture was heated to reflux for 12 hours The mixture was then cooled to room temperature. and concentrated in vacuo. The resulting foam was dissolved in water, alkalinized with 1 N sodium hydroxide and the resulting white solid It was filtered, washed with water and dried. This provided 50 g of a white solid that recrystallized with wet ethyl acetate / hexane, providing the title compound, melting point: 160.5-162.0 ° C.

The title compounds of the example 2-130 were prepared by a procedure analogous to that described in example 1, using the reagents indicated.

Example 2 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3- (1-hydroxycyclopentyl) benzenesulfonyl] urea

3-1-Hydroxycyclopentylbenzenesulfonamide; 4-chloro-2,6-diisopropylphenylisocyanate. Mp .: 155 ° C.

Example 3 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3-methylsulfamoylbenzenesulfonyl] urea

3-Methylsulfamoylbenzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate.  Mp .: 125-128 ° C.

Example 4 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3-dimethylsulfamoylbenzenesulfonyl] urea

3-Dimethylsulfamoylbenzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate.  Mp .: 101-106 ° C.

Example 5 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3-cyclopropylsulfamoylbenzenesulfonyl] urea

3-Cyclopropylsulfamoylbenzenesulfonamide; 4-chloro-2,6-diisopropyl-phenylisocyanate. Mp .: 170-174 ° C.

Example 6 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3-cyclobutyl sulfamoylbenzenesuylphonyl] urea

3-Cyclobutyl sulfamoylbenzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate.  Mp .: 140-143 ° C.

Example 7 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3-methylsulfanylbenzenesulfonyl] urea

3-Methylsulfanylbenzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 125-126 ° C.

Example 8 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3- (methanesulfinylbenzenesulfonyl] urea

3-Methylsulfinylbenzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 226-227 ° C.

Example 9 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3-methanesulfonylbenzenesulfonyl] urea

3-Methylsulfonylbenzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. P.f. ºC.

Example 10 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3- (1-idroxycyclobutyl) benzenesulfonyl] urea

3-1-Hydroxycyclobutylbenzenesulfonylamide; 4-chloro-2,6-diisopropylphenyl isocyanate.  Mp .: 155-157 ° C.

Example 11 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3- (1-droxycyclopentyl) benzenesulfonyl] urea

3-1-Hydroxycyclopentylbenzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 155 ° C.

Example 12 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3- (1-idroxycyclohexyl) benzenesulfonyl] urea

3-1-Hydroxycyclohexylbenzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 172-176 ° C.

Example 13 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3- (2-methyl- [1,3] -dioxolan-2-yl) benzenesulfonyl] -urea

3- (2-Methyl- [1,3] -dioxolan-2-yl) benzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 155-157 ° C.

Example 14 1- (4-Chloro-2,6-diisopropylphenyl) -3- (3- [1,3] -dioxolan-2-ylbenzenesulfonyl] urea

3 - ([1,3] -Dioxolan-2-yl) benzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 145-147 ° C.

Example 15 1- (4-Chloro-2,6-diisopropylphenyl) -3- (2-fluoro-5- (2-methyl- [1,3] -dioxolan-2-yl) benzene-sulfonyl] urea

3- (2-Fluoro-5- (2-methyl- [1,3] -dioxolan-2-yl) benzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 168-170 ° C.

Example 16 1- [2-Fluoro-5- (2-methyl- (1,3) -dioxolan-2-yl) benzenesulfonyl] -3- (1,2,3,5,6,7-hexa-hydro-5- indacen-4-il) urea Example 17 1- (4-Chloro-2,6-diisopropylphenyl) -3- [1H-indole-6-sulfonyl] urea

3- (1H-Indol-6-sulfonamide) benzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 220-221 ° C.

Example 18 1- (1,2,3,5,6,7-Hexahydro-5-indacen-4-yl) -3- [1 H -indole-6-sulfonyl] urea Example 19 1- (4-Chloro-2,6-diisopropylphenyl) -3- (5-fluoro-1 H -indole-6-sulfonyl] urea

3- (5-Fluoro-1 H -indole-6-sulfonamide) benzenesulfonamide; 4-chloro-2, 6-diisopropylphenyl isocyanate. Mp: 226-227 ° C.

Example 20 1- [5-Fluoro-1 H -indole-6-sulfonyl] -3- (1,2,3,5,6,7-hexahydro-5-indacen-4-yl) urea Example 21 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3- (1-hydroxyethyl) -5-trifluoromethylbenzene-sulfonyl] urea

3- (1-Hydroxyethyl) -5-trifluoromethylbenzenesulfonamide; 4-chloro-2, 6-diisopropylphenyl isocyanate. P.f .: 168.9-170.0 ° C.

Example 22 1- (3-Acetyl-5-trifluoromethylbenzenesulfonyl] -3- (4-chloro-2, 6-diisopropylphenyl) urea

3-Acetyl-5-trifluoromethylbenzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 157.4-158.9 ° C.

Example 23 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3- (1-hydroxyethyl) -4-methylbenzenesulfonyl] urea

3- (1-Hydroxyethyl) -4-methylbenzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 155.2-158.2 ° C.

Example 24 1- (3-Acetyl-4-methylbenzenesulfonyl) -3- (4-chloro-2,6-diisopropylphenyl) urea

3-Acetyl-4-methylbenzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 152.5-154.6 ° C.

Example 25 1- [3,5-Bis- (1-hydroxyethyl) benzenesulfonyl] -3- (4-chloro-2, 6-diisopropylphenyl) urea

3,5-Bis- (1-hydroxyethyl) benzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 175.3-176.8 ° C.

Example 26 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3- (1-hydroxyethyl) -5-iodobenzenesulfonyl] urea

3- (1-Hydroxyethyl) -5-iodobenzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 184.4-186.6 ° C.

Example 27 1- (3-Acetyl-5-iodobenzenesulfonyl) -3- (4-chloro-2,6-diisopropylphenyl) urea

3-Acetyl-5-iodobenzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 187.6-188.9 ° C.

Example 28 1- (4-Chloro-2,6-diisopropylphenyl) -3- [4-fluoro-3 - (1-hydroxyethyl) benzenesulfonyl] urea

4-Fluoro-3- (1-hydroxyethyl) benzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 149.7-151.8 ° C.

Example 29 1- (3-Acetyl-4-fluorobenzenesulfonyl) -3- (4-chloro-2,6-diisopropylphenyl) urea

3-Acetyl-4-fluorobenzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 171.8-173.4 ° C.

Example 30 1- (4-Acetylthiophene-2-sulfonyl) -3- (4-chloro-2,6-diisopropylphenyl) urea

4-Acetylthiophene-2-sulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 169.1-171.8 ° C.

Example 31 1- (4-Chloro-2,6-diisopropylphenyl) -3- [4- (1-hydroxyethyl) thiophene-2-sulfonyl] urea

4- (1-Hydroxyethyl) thiophene-2-sulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 164.5-166.6 ° C.

Example 32 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3- (2-hydroxyiminopropyl) benzenesulfonyl] urea

3- (2-Hydroxyiminopropyl) benzenesulfonyl; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 153.8-156.7 ° C.

Example 33 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3- (2-hydroxypropyl) benzenesulfonyl] urea

3- (2-Hydroxypropyl) benzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 148.7-149.9 ° C.

Example 34 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3- (2-oxopropyl) benzenesulfonyl] urea

3- (2-Oxopropyl) benzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 154.8-156.6 ° C.

Example 35 1- (2,6-Diisopropylphenyl) -3- (3-propionylbenzenesulfonyl) urea

3-Propionylbenzenesulfonamide; 2,6-diisopropylphenyl isocyanate. P.f .: 151.7-152.8 ° C.

Example 36 1- (3-Acetyl-4-methoxybenzenesulfonyl) -3- (4-chloro-2,6-diisopropylphenyl) urea

3-Acetyl-4-methoxybenzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 214.2-215.1 ° C.

Example 37 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3- (1-hydroxyethyl) -4-methoxybenzenesulfonyl] urea

3- (1-Hydroxyethyl) -4-methoxybenzenesulfonamide; 4-chloro-2,6-diisopropyl-phenylisocyanate. Mp .: 164.9-166.1 ° C.

Example 38 1- (4-Chloro-2,6-diisopropylphenyl-3- [3- (1-hydroxypropyl) benzenesulfonyl] urea

3- (1-Hydroxypropyl) benzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 218.4-220.3 ° C.

Example 39 1- (4-Chloro-2,6-diisopropylphenyl) -3- (3-propionylbenzenesulfonyl) urea

3-Propionylbenzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 149.1-152.2 ° C.

Example 40 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3- (1-hydroxyethyl) benzenesulfonyl] urea

3- (1-Hydroxyethyl) benzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 151.8-154.3 ° C.

Example 41 1- (5-Acetyl-2-methoxybenzenesulfonyl) -3- (4-bromo-2,6-diisopropylphenyl) urea

5-Acetyl-2-methoxybenzenesulfonamide; 4-Bromo-2,6-diisopropylphenyl isocyanate. Mp .: 185.1-186.5 ° C.

Example 42 1- (5-Acetyl-2-methoxybenzenesulfonyl) -3- (2,6-diisopropylphenyl) urea

5-Acetyl-2-methoxybenzenesulfonamide; 2,6-diisopropylphenyl isocyanate. P.f .: 199.7-201.3 ° C.

Example 43 1- (3-Acetylbenzenesulfonyl) -3- (4-chloro-2,6-diisopropylphenyl) urea

3-Acetylbenzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 163.1-165.6 ° C.

Example 44 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3- (1-hydroxyiminoethyl) benzenesulfonyl] urea

3- (1-Hydroxyiminoethyl) benzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 154.8-160.0 ° C.

Example 45 1- (4-Bromo-2,6-diisopropylphenyl) -3- (6-methyl-1,1-dioxo-1-thiochroman-7-sulfonyl) urea

6-Methyl-1,1-dioxo-1-thiochroman-7-sulfonamide; 4-Bromo-2,6-diisopropylphenyl isocyanate. Mp .: 250.4-251.9 ° C.

Example 46 1- (2,6-Diisopropylphenyl) -3- (6-methyl-1,1-dioxo-1-thiochroman-7-sulfonyl) urea

6-Methyl-1,1-dioxo-1-thiochroman-7-sulfonamide;  2,6-diisopropylphenyl isocyanate. P.f .: 242.7-245.2 ° C.

Example 47 1- (2,6-Diisopropylphenyl) -3- [3- (1-hydroxyethylbenzenesulfononyl] urea

3- (1-Hydroxyethyl) benzenesulfonamide;  2,6-diisopropylphenyl isocyanate. Mp .: 122.6-124.0 ° C.

Example 48 1- (4-Bromo-2,6-diisopropylphenyl) -3- [3- (1-hydroxyethyl) benzenesulfonyl] urea

3- (1-Hydroxyethyl) benzenesulfonamide; 4-Bromo-2,6-diisopropylphenyl isocyanate. Mp .: 142.5-144.80 ° C.

Example 49 1- (3-Acetylbenzenesulfonyl) -3- (4-bromo-2,6-diisopropylphenyl) urea

3-Acetylbenzenesulfonamide; 4-Bromo-2,6-diisopropylphenyl isocyanate. Mp .: 231.4-233.6 ° C.

Example 50 1- (3-Acetyl-4-hydroxybenzenesulfonyl) -3- (2,6-diisopropylphenyl) urea

3-Acetyl-4-hydroxybenzenesulfonamide;  2,6-diisopropylphenyl isocyanate. P.:196.8-198.90 ° C.

Example 51 1- (3-Acetyl-4-methoxybenzenesulfonyl) -3- (2,6-diisopropylphenyl) urea

3-Acetyl-4-methoxybenzenesulfonamide;  2,6-diisopropylphenyl isocyanate. Mp .: 203.4-205.7 ° C.

Example 52 1- (3-Acetylbenzenesulfonyl) -3- (2- sec -butyl-6-ethylphenyl) urea

3-Acetylbenzenesulfonamide; 2- sec -butyl-6-ethylphenyl isocyanate. Mp: 136.3-138.9 ° C.

Example 53 1- (3-Acetylbenzenesulfonyl) -3- (2-isopropyl-6-methylphenyl) urea

3-Acetylbenzenesulfonamide; 2-Isopropyl-6-methylphenyl isocyanate. Mp .: 136, 8-138.9 ° C.

Example 54 1- (3-Acetylbenzenesulfonyl) -3- (2- tert -butyl-6-methylphenyl) urea

3-Acetylbenzenesulfonamide; 2- tert -butyl-6-methylphenyl isocyanate. Mp: 155.4-157.7 ° C.

Example 55 1- (3-Acetylbenzenesulfonyl) -3- (2-ethyl-6-isopropylphenyl) urea

3-Acetylbenzenesulfonamide; 2-ethyl-6-isopropylphenyl isocyanate. Mp .: 127.1-128.5 ° C.

Example 56 1- (3-Acetylbenzenesulfonyl) -3- (2,6-diisopropylphenyl) urea

3-Acetylbenzenesulfonamide, 2,6-diisopropylphenyl isocyanate. P.f .: 151.6-153.5 ° C.

Example 57 1- (4-Acetyl-2,6-diisopropylphenyl) -3- (3,5-diacetylbenzenesulfonyl) urea

3,5-Diacetylbenzenesulfonamide; 4-acetyl-2,6-diisopropylphenyl isocyanate. Mp .: 154.0-156.40 ° C.

Example 58 4- [3- (3,5-Diacetylbenzenesulfonyl) ureido] -3,5-diisopropylbenzamide

3,5-Diacetylbenzenesulfonamide; 4-isocyanate-3,5-diisopropylbenzamide. Mp .: 198.5-199.8 ° C.

Example 59 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3- (2,2,2-trifluoro-1-hydroxyethyl) benzenesulfonyl] -urea

3- (2,2,2-Trifluoro-1-hydroxyethyl) benzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 129.6-131.5 ° C.

Example 60 1- (4-Chloro-2,6-diisopropylphenyl) -3- (3-trifluoroacetylbenzenesulfonyl) urea

3-Trifluoroacetylbenzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 88.4-89.1 ° C.

Example 61 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3- (1-hydroxy-2-methoxyethyl) benzosulfonyl] urea

3- (1-Hydroxy-2-methoxyethyl) benzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 108.7-109.2 ° C.

Example 62 1- (4-Chloro-2,6-diisopropylphenyl) -3- (3-methoxyacetylbenzenesulfonyl) urea

3-Methoxyacetylbenzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 121.2-122.1 ° C.

Example 63 4- [3- (3- (1-Hydroxyethyl) benzenesulfonyl] ureido] -3,5-diisopropylbenzamide

3- (1-Hydroxyethyl) benzenesulfonamide; 4-isocyanate-3,5-diisopropylbenzamide. Mp .: 204.6-205.9 ° C.

Example 64 1- (4-Cyano-2,6-diisopropylphenyl) -3- [3- (1-hydroxyethyl) benzenesulfonyl] urea

3- (1-Hydroxyethyl) benzenesulfonamide; 4-cyano-2,6-diisopropylphenyl isocyanate. Mp .: 191.3-194.0 ° C.

Example 65 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3- (1-hydroxy-2-methylpropyl) benzenesulfonyl] urea

3- (1-Hydroxy-2-methylpropyl) benzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 152.3-153.0 ° C.

Example 66 1- (4-Chloro-2,6-diisopropylphenyl) -3- (3-isobutyrylbenzenesulfonyl) urea

3-Isobutyrylbenzenesulfonamide, 4-chloro-2,6-diisopropylphenyl isocyanate. P.f. 170.2-171.4 ° C.

Example 67 1- (2,6-Diisopropyl-4-thiophene-3-ylphenyl) -3- [3- (1-hydroxyethyl) benzenesulfonyl] urea

3- (1-Hydroxyethyl) benzenesulfonamide; 2,6-diisopropyl-4-thiophene-3-ylphenyl isocyanate. Mp .: 137.0-139.4 ° C.

Example 68 1- (2,6-Diisopropyl-4-thiophene-2-ylphenyl) -3- [3- (1-hydroxyethyl) benzenesulfonyl] urea

3- (1-Hydroxyethyl) benzenesulfonamide; 2,6-diisopropyl-4-thiophene-2-ylphenyl isocyanate. Mp .: 98.4-99.9 ° C.

Example 69 1- (3,5-Diisopropylbiphenyl-4-yl) -3- [3- (1-hydroxyethyl) benzenesulfonyl] urea

3- (1-Hydroxyethyl) benzenesulfonamide; 4-isocyanate-3,5-diisopropylbiphenyl. Mp .: 127.4-128.6 ° C.

Example 70 1- (4-Chloro-2,6-diisopropylphenyl) -3- (8-hydroxy-5,6,7, 8-tetrahydronaphthalen-2-sulfonyl) -urea

8-Hydroxy-5,6,7,8-tetrahydronaphthalen-2-sulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate.  Mp .: 136.8-138.2 ° C.

Example 71 1- (4-Chloro-2,6-diisopropylphenyl) -3- (8-oxo-5,6,7,8-tetrahydronaphthalen-2-sulfonyl) -urea

8-Oxo-5,6,7,8-tetrahydronaphthalen-2-sulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 180.0-182.4 ° C.

Example 72 1- (4-Chloro-2,6-diisopropylphenyl) -3- (8-hydroxyimino-5,6,7, 8-tetrahydronaphthalen-2-sulfonyl) urea

8-Hydroxyimino-5,6,7,8-tetrahydronaphthalen-2-sulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 162.5-164.2 ° C.

Example 73 1- (4-Bromo-2,6-diisopropylphenyl) -3- (8-hydroxy-5,6,7, 8-tetrahydronaphthalen-2-sulfonyl) urea

8-Hydroxy-5,6,7,8-tetrahydronaphthalen-2-sulfonamide; 4-Bromo-2,6-diisopropylphenyl isocyanate. Mp .: 164.0-165.8 ° C.

Example 74 1- (2,6-Diisopropylphenyl) -3- (8-hydroxy-5,6,7, 8-tetrahydronaphthalen-2-sulfonyl) urea

8-Hydroxy-5,6,7,8-tetrahydronaphthalen-2-sulfonamide;  2,6-diisopropylphenyl isocyanate. P.f .: 120.0-122.6 ° C.

Example 75 1- (2,6-Diisopropylphenyl) -3- (8-hydroxyimino-5,6,7, 8-tetrahydronaphthalen-2-sulfonyl) -urea

8-Hydroxyimino-5,6,7,8-tetrahydronaphthalen-2-sulfonamide;  2,6-diisopropylphenyl isocyanate. P.f .: 139.2-140.0 ° C.

Example 76 1- (4-Bromo-2,6-diisopropylphenyl) -3- (8-hydroxyimino-5,6,7, 8-tetrahydronaphthalen-2-sulfonyl) urea

8-Hydroxyimino-5,6,7,8-tetrahydronaphthalen-2-sulfonamide; 4-Bromo-2,6-diisopropylphenyl isocyanate. Mp .: 168.6-169.2 ° C.

Example 77 1- (4-Bromo-2,6-diisopropylphenyl) -3- (8-oxo-5,6,7,8-tetrahydronaphthalen-2-sulfonyl) -urea

8-Oxo-5,6,7,8-tetrahydronaphthalen-2-sulfonamide; 4-Bromo-2,6-diisopropylphenyl isocyanate. Mp .: 208.0-208.8 ° C.

Example 78 1- (2,6-Diisopropylphenyl) -3- (8-oxo-5,6,7,8-tetrahydronaphthalen-2-sulfonyl) urea

8-Oxo-5,6,7,8-tetrahydronaphthalen-2-sulfonamide;  2,6-diisopropylphenyl isocyanate. P.f .: 197.4-198.0 ° C.

Example 79 3- [3- (4-Bromo-2,6-diisopropylphenyl) ureidosulfonyl] benzamide

3-Sulfonamidobenzamide; 4-Bromo-2,6-diisopropylphenyl isocyanate.  Mp .: 180.0-180.6 ° C.

Example 80 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3- (1,2-dihydroxyethyl) benzenesulfonyl] urea

3- (1,2-Dihydroxyethyl) benzenesulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 169.7-171.2 ° C.

Example 81 3- [3- (2,6-Diisopropylphenyl) ureidosulfonyl] benzamide

3-Sulfonamidobenzamide; 2,6-diisopropylphenyl isocyanate. P.f .: 182.3-184.1 ° C.

Example 82 3- [3- (4-Bromo-2,6-diisopropylphenyl) ureidosulfonyl] - N -methylbenzamide

3-Sulfonamido-N-methylbenzamide; 4-Bromo-2,6-diisopropylphenyl isocyanate. Mp .: 243.8-245.1 ° C.

Example 83 3- [3- (2,6-Diisopropylphenylureidosulfonyl] - N -methylbenzamide

3-Sulfonamido- N- methylbenzamide; 2,6-diisopropylphenyl isocyanate. Mp: 236.2-237.2 ° C.

Example 84 1- (5-Acetyl-2-bromobenzenesulfonyl) -3- (4-bromo-2,6-diisopropylphenyl) urea

5-Acetyl-2-bromobenzenesulfonamide; 4-Bromo-2,6-diisopropylphenyl isocyanate.  Mp .: 177.2-179.1 ° C.

Example 85 1- [2-Chloro-5- (1-hydroxyethyl) benzenesulfonyl] -3- (2,6-diisopropylphenyl) urea

2-Chloro-5- (1-hydroxyethyl) benzenesulfonamide; 2,6-diisopropylphenyl isocyanate. P.f .: 154.0-156.0 ° C.

Example 86 1- [2-Chloro-5- (1-hydroxyethyl) benzenesulfonyl] -3- (4-bromo-2, 6-diisopropylphenyl) urea

2-Chloro-5- (1-hydroxyethyl) benzenesulfonamide; 4-Bromo-2,6-diisopropylphenyl isocyanate. Mp .: 144.3-146.2 ° C.

Example 87 1- [2-Chloro-5- (1-hydroxyiminoethyl) benzenesulfonyl] -3- (2, 6-diisopropylphenyl) urea

2-Chloro-5- (1-hydroxyiminoethyl) benzenesulfonamide;  2,6-diisopropylphenyl isocyanate. P.f .: 156.6-158.0 ° C.

Example 88 1- [2-Chloro-5- (1-hydroxyiminoethyl) benzenesulfonyl] -3- (4-bromo-2, 6-diisopropylphenyl) -urea

2-Chloro-5- (1-hydroxyiminoethyl) benzenesulfonamide; 4-Bromo-2,6-diisopropylphenyl isocyanate. Mp .: 185.0-186.2 ° C.

Example 89 1- (5-Acetyl-2-chlorobenzenesulfonyl) -3- (2,6-diisopropylphenyl) urea

5-Acetyl-2-chlorobenzenesulfonylamide;  2,6-diisopropylphenyl isocyanate. Mp .: 180,7-182.3 ° C.

Example 90 1- (5-Acetyl-2-chlorobenzenesulfonyl) -3- (4-bromo-2,6-diisopropylphenyl) urea

5-Acetyl-2-chlorobenzenesulfonamide; 4-Bromo-2,6-diisopropylphenyl isocyanate. Mp .: 175.2-176.5 ° C.

Example 91 3- [3- (2,6-Diisopropylphenyl) ureidosulfonyl] - N , N -dimethylbenzamide

3-Sulfonamido- N , N -dimethylbenzamide; 2,6-diisopropylphenyl isocyanate. Mp: 211.8-212.5 ° C.

Example 92 3- [3- (4-Bromo-2,6-diisopropylphenyl) ureidosulfonyl] -N, N-dimethylbenzamide

3-Sulfonamido- N , N -dimethylbenzamide; 4-Bromo-2,6-diisopropylphenyl isocyanate. Mp: 225.7-227.6 ° C.

Example 93 1- (2,6-Diisopropylphenyl) -3- (3-formylbenzenesulfonyl) urea

3-Formylbenzenesulfonamide; 2,6-diisopropylphenyl isocyanate. P.f .: 108.3-109.0 ° C.

Example 94 1- [2,6-Diisopropyl (hydroxyiminomethyl) benzenesulfonyl] urea

3- (Hydroxyiminomethyl) benzenesulfonamide; 2,6-diisopropylphenyl isocyanate. P.f .: 107.0-108.1 ° C.

Example 95 1- (2,6-Diisopropylphenyl) -3- [3- (1-methoxyiminoethyl) benzenesulfonyl] urea

3- (1-Methoxyiminoethyl) benzenesulfonamide; 2,6-diisopropylphenyl isocyanate. P.f .: 164.9-165.9 ° C.

Example 96 1- [3- (1-Benzyloxyiminoethyl) benzenesulfonyl] -3- (2,6-diisopropylphenyl) urea

3- (1-Benzyloxyiminoethyl) benzenesulfonamide;  2,6-diisopropylphenyl isocyanate. P.f .: 136.5-139.0 ° C.

Example 97 1- (2,6-Diisopropylphenyl) -3- [3- (1-ethoxyiminoethyl) benzenesulfonyl] urea

3- (1-Ethoxyiminoethyl) benzenesulfonamide; 2,6-diisopropylphenyl isocyanate. P.f .: 156.9-158.4 ° C.

Example 98 Acid (1- {3- [3- (2, 6-diisopropylphenyl) ureidosulfoni] phenyl} ethylidenaminooxy) acetic

Acid 3-sulfonamidophenyl- (1-ethylidenaminooxy) acetic acid; 2,6-diisopropyl-phenylisocyanate. P.f. 107.1-107.7 ° C.

Example 99 1- (2,6-Diisopropylphenyl) -3- [3- (1-hydroxyiminoethyl) benzenesulfonyl] urea

3- (1-Hydroxyiminoethyl) benzenesulfonamide; 2,6-diisopropylphenyl isocyanate. P.f .: 131.0-132.6 ° C.

Example 100 1- (2,6-Diisopropylphenyl) -3- (3-methanesulfonylbenzenesulfonyl) urea

3-Methanesulfonylbenzenesulfonamide; 2,6-diisopropylphenyl isocyanate. P.f .: 99.5-100.6 ° C.

Example 101 1- (2,6-Diisopropylphenyl) -3- (3-methanesulfinylbenzenesulfonyl) urea

3-Methanesulfinylbenzenesulfonamide; 2,6-diisopropylphenyl isocyanate. P.f .: 217.4-221.0 ° C.

Example 102 3- [3- (2,6-Diisopropylphenyl) ureidosulfonyl] benzenesulfonamide

3-Sulfonamidobenzenesulfonamide; 2,6-diisopropylphenyl isocyanate. P.f .: 131.4-133.5 ° C.

Example 103 1- (4-Bromo-2,6-diisopropylphenyl) -3- (3-formylbenzenesulfonyl) urea

3-Formylbenzenesulfonamide; 4-Bromo-2,6-diisopropylphenyl isocyanate. Mp .: 127.2-128.6 ° C.

Example 104 1- [3- (2-Acetylphenoxymethyl) benzenesulfonyl] -3- (2,6-diisopropylphenyl) urea

3- (2-Acetylphenoxymethyl) benzenesulfonamide; 2,6-diisopropylphenyl isocyanate. P.f .: 124.2-125 ° C.

Example 105 Hydrochloride 1- [3- (1-aminoethyl) benzenesulfonyl] -3- (2, 6-diisopropylphenyl) urea

Hydrochloride 3- (1-aminoethyl) benzenesulfonamide; 2,6-diisopropylphenyl isocyanate. P.f .: 210.6-212.9 ° C.

Example 106 1- (2,6-Diisopropylphenyl) -3- (3-furan-2-ylbenzenesulfonyl) urea

3-Furan-2-ylbenzenesulfonamide; 2,6-diisopropylphenyl isocyanate. P.f .: 196.6-198.0 ° C.

Example 107 1- (2,6-Diisopropylphenyl) -3- (4-furan-2-ylbenzenesulfonyl) urea

4-Furan-2-ylbenzenesulfonamide; 2,6-diisopropylphenyl isocyanate. P.f .: 201.5-202.7 ° C.

Example 108 1- (1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) -3- [4- (1-hydroxyimino) ethyl) thiophene-2-sulfonyl] urea

4- (1-Hydroxyiminoethyl) thiophene-2-sulfonamide; 4-Isocyanate-1,2,3,5,6,7-hexahydro-s-indacene: Mp .: 261.8-266.1 ° C.

Example 109 1- (4-Acetylthiophene-2-sulfonyl) -3- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) urea

4-Acetylthiophene-2-sulfonamide; 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene. Mp .: 270.2-272.3 ° C.

Example 110 1- (1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) -3- [5- (1-hydroxy-1-methylethyl) thiophene-3-sulfonyl] urea

5- (1-Hydroxy-1-methylethyl) thiophene-3-sulfonamide; 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene.  Mp .: 149.5-154.8 ° C.

Example 111 1- (2,6-Diisopropylphenyl) -3- [4- (1-hydroxy-1-methylethyl) thiophene-2-sulfonyl] urea

4- (1-Hydroxy-1-methylethyl) thiophene-2-sulfonamide; 2,6-diisopropylphenyl isocyanate. P.f .: 124.6-127.4 ° C.

Example 112 1- (2,6-Diisopropylphenyl) -3- [4- (1-hydroxy-1-methylethyl) furan-2-sulfonyl] urea

4- (1-Hydroxy-1-methylethyl) furan-2-sulfonamide; 2,6-diisopropylphenyl isocyanate. P.f .: 121.13-126.4 ° C.

Example 113 1- (1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) -3- [4- (1-hydroxy-1-methylethyl) thiophene-2-sulfonyl] urea

4- (1-Hydroxy-1-methylethyl) thiophene-2-sulfonamide; 4-isocyanate-1,2,3,5,6, 7-hexahydro-s-indacene. Mp .: 133.1-134.0 ° C.

Example 114 1- (1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) -3- [4- (1-hydroxy-1-methylethyl) furan-2-sulfonyl] urea

4- (1-Hydroxy-1-methylethyl) furan-2-sulfonamide; 4-isocyanate-1,2,3,5,6, 7-hexahydro-s-indacene. Mp .: 153.8-154.4 ° C.

Example 115 1- (8-Chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl) -3- [4- (1-hydroxy-1-methylethyl) furan-2-sulfonyl] urea

4- (1-Hydroxy-1-methylethyl) furan-2-sulfonamide; 4-Chloro-8-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene. Mp .: 163.7 ° C (decomposed).

Example 116 1- (4-Formylfuran-2-sulfonyl) -3- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) urea

4-Formylfuran-2-sulfonamide; 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene.  Mp .: 281.3-284.1 ° C.

Example 117 1- (1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) -3- (4-hydroxymethylthiophene-2-sulfonyl) urea

4-Hydroxymethylthiophene-2-sulfonamide; 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene. Mp .: 273.9-275.8 ° C.

Example 118 1- (4-Formylthiophene-2-sulfonyl) -3- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) urea

4-Formylthiophene-2-sulfonamide; 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene.  Mp .: 146.3-148.9 ° C.

Example 119 1- (4-Chloro-2,6-diisopropylphenyl) -3- [4- (1-hydroxyiminoethyl) thiophene-2-sulfonyl] urea

4- (1-Hydroxyiminoethyl) thiophene-2-sulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 184.7-187.8 ° C.

Example 120 1- (4-Chloro-2,6-diisopropylphenyl) -3- [5- (1-hydroxy-1-methylethyl) furan-2-sulfonyl] urea

5- (1-Hydroxy-1-methylethyl) furan-2-sulfonamide; 4-Chloro-2,6-diisopropylphenyl isocyanate. Mp .: 116.0-117.9 ° C.

Example 121 1- (4-Chloro-2,6-diisopropylphenyl) -3- [4- (1-hydroxy-1-methylethyl) furan-2-sulfonyl] urea

4- (1-Hydroxy-1-methylethyl) furan-2-sulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 127.4-129.2 ° C.

Example 122 1- (4-Chloro-2,6-diisopropylphenyl) -3- [4- (1-hydroxy-1-methylethyl) thiophene-2-sulfonyl] urea

4- (1-Hydroxy-1-methylethyl) thiophene-2-sulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 131.2-133.6 ° C.

Example 123 1- (4-Chloro-2,6-diisopropylphenyl) -3- [5- (1-hydroxy-1-methylethyl) thiophene-2-sulfonyl] urea, sodium salt

5- (1-Hydroxy-1-methylethyl) thiophene-2-sulfonamide; 4-chloro-2,6-diisopropylphenyl isocyanate. Mp .: 270.3-271.9 ° C.

Example 124 1- (4- [1,3] -Dioxolan-2-ilthiophe-2-sulfonyl) -3- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) urea

4- [1,3] -Dioxolan-2-ylthiophen-2-sulfonamide; 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene. Mp .: 224.7-226.6 ° C.

Example 125 1- (4- [1,3] -Dioxolan-2-ilfuran-2-sulfonyl) -3- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) urea

4- [1,3] -Dioxolan-2-ylfuran-2-sulfonamide; 4-Isocyanate-1,2,3,5,6,7-hexa-hydro-s-indacene. Mp .: 183.5 ° C (decomposition).

Example 126 1- [3- (4,5-Dihydro-1 H -imidazol-2-yl) benzenesulfonyl-3- (1,2,3,5,6, 7-hexahydro-s-indacen-4-yl) urea

3- (4,5-Dihydro-1 H -imidazol-2-yl) benzenesulfonamide; 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene. Mp: 241.0 ° C (decomposition).

Example 127 1- (1 H -Bencimidazol-5-sulfonyl) -3- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) urea

1 H -Benzoimidazol-5-sulfonamide; 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene. Mp: 239.0 ° C (decomposition).

Example 128 1- (1,2,3,5,6,7-Hexahydro-s-indacen-4-yl) -3- [3- (1-hydroxyiminoethyl) benzene-sulfonyl] urea

3- (1-Hydroxyiminoethyl) benzenesulfonamide; 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indacene. Mp .: 249.8 ° C (decomposition).

Example 129 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3- tert -butylsulfamoylbenzenesulfonyl] urea

Benzene-1,3-disulfonic acid tert -butylamide; 5-Chloro-2-isocyanate-1,3-diisopropylbenzene.

Example 130 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3-sulfamoylbenzenesulfonyl] urea.

Using a procedure similar to that of Preparation G, starting from 200 mg (0.38 mmol) of 1- (4-chloro-2,6-diisopropylphenyl) -3- [3- tert-butyl sulfulfylbenzenesulfonyl] urea, 92 were obtained mg of the title compound as a white solid. Mp: 172-177 ° C.

Claims (4)

1. A compound selected from the group Constituted by: 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3- (1-hydroxy-1-methylethyl) benzenesulfonyl] -urea; 1- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) -s- [4- (1-hydroxy-1-methylethyl) furan-2-sulfonyl] urea; 1- (1,2,3,5,6,7-hexahydro-4-aza-s-indacen-8-yl) -3- [4- (1-hydroxy-1-methylethyl) -furan-2-sulfonyl ]urea; 1- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) -3- [4- (1-hydroxy-1-methyl) ethyl] thiophene-2-sulfonyl] urea; 1- (4- [1,3] -dioxolan-2-ylfuran-2-sulfonyl) -3- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) urea; 1- (2,6-diisopropylphenyl) -3- [4- (1-hydroxy-1-methylethyl) furan-2-sulfonyl] urea; 1- (2,6-diisopropylphenyl) -3- [4- (1-hydroxy-1-methylethyl) thiophene-2-sulfonyl] urea; 1- (4-acetylthiophene-2-sulfonyl) -3- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) urea; 1- (1 H -benzimidazol-5-sulfonyl) -3- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) urea; 1- (1,2,3,4,5,6,7-hexahydro-s-indacen-4-yl) -3- [4- (1-hydroxy-1-methylethyl) thiophene-2-sulfonyl] urea; 1- (8-Chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl) -3- [4- (1-hydroxy-1-methylethyl) furan-2-sulfonyl] urea; 1- (4-acetylfuran-2-sulfonyl) -3- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) urea; 1- (8-Fluoro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl) -3- [4- (11-hydroxy-1-methylethyl) furan-2-sulfonyl] urea; 1- (4-fluoro-2,6-diisopropylphenyl) -3- [3- (1-hydroxy-1-methylethyl) benzenesulfonyl] -urea; 1- (6-Fluoro-1 H -benzimidazol-5-sulfonyl) -3- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) urea; 1- (4-Chloro-2,6-diisopropylphenyl) -3- (1 H -indole-6-sulfonyl) urea; 1- (4-Chloro-2,6-diisopropylphenyl) -3- (5-fluoro-1 H -indole-6-sulfonyl) urea; 1- [1,2,3,5,6,7-hexahydro-s-indacen-4-yl) -3- (1 H -indole-6-sulfonyl) urea; 1- (5-Fluoro-1 H -indole-6-sulfonyl) -3- (1,2,3,5,6,7-hexahydro-5-indacen-4-yl) urea; 1- [4-Chloro-2,6-diisopropylphenyl] -3- [2-fluoro-5- (2-methyl- (1,3) -dioxolan-2-yl) benzenesulfonyl] urea; 1- [4-Chloro-2,6-diisopropylphenyl] -3- [3-methylsulfamoylbenzenesulfonyl] urea; 1- [2-Fluoro-5- (2-methyl- (1,3) -dioxolan-2-yl) benzenesulfonyl] -3-1,2,3,5,6, 7-hexahydroindacen-4-yl) urea; Y 3- [3- (1,2,3,5,6,7-hexahydro-S-indacen-4-yl) ureidosulfonyl] - N -methyl-benzenesulfonamide. or a pharmaceutically acceptable salt of same. 2. A compound according to claim 1, which is select from the group consisting of 1- (4-Chloro-2,6-diisopropylphenyl) -3- [3- (1-hydroxy-1-methylethyl) benzenesulfonyl] -urea; 1- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) -s- [4- (1-hydroxy-1-methylethyl) furan-2-sulfonyl] urea; 1- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) -3- [4- (1-hydroxy-1-methyl) ethyl] thiophene-2-sulfonyl] urea; 1- (4- [1,3] -dioxolan-2-ylfuran-2-sulfonyl) -3- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) urea; 1- (2,6-diisopropylphenyl) -3- [4- (1-hydroxy-1-methylethyl) furan-2-sulfonyl] urea; 1- (2,6-diisopropylphenyl) -3- [4- (1-hydroxy-1-methylethyl) thiophene-2-sulfonyl] urea; 1- (4-acetylthiophene-2-sulfonyl) -3- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) urea; 1- (1 H -benzimidazol-5-sulfonyl) -3- (1,2,3,5,6,7-hexahydro-s-indacen-4-yl) urea; 1- (1,2,3,4,5,6,7-hexahydro-s-indacen-4-yl) -3- [4- (1-hydroxy-1-methylethyl) thiophene-2-sulfonyl] urea; 1- (8-Chloro-1,2,3,5,6,7-hexahydro-s-indacen-4-yl) -3- [4- (1-hydroxy-1-methylethyl) furan-2-sulfonyl] urea; 1- (4-Chloro-2,6-diisopropylphenyl) -3- (1 H -indole-6-sulfonyl) urea; 1- (4-Chloro-2,6-diisopropylphenyl) -3- (5-fluoro-1 H -indole-6-sulfonyl) urea; 1- [1,2,3,5,6,7-hexahydro-s-indacen-4-yl) -3- (1 H -indole-6-sulfonyl) urea; 1- (5-Fluoro-1 H -indole-6-sulfonyl) -3- (1,2,3,5,6,7-hexahydro-5-indacen-4-yl) urea; 1- [4-Chloro-2,6-diisopropylphenyl] -3- [2-fluoro-5- (2-methyl- (1,3) -dioxolan-2-yl) benzenesulfonyl] urea; 1- [4-Chloro-2,6-diisopropylphenyl] -3- [3-methylsulfamoylbenzenesulfonyl] urea; Y 1- [2-Fluoro-5- (2-methyl- (1,3) -dioxolan-2-yl) benzenesulfonyl] -3-1,2,3,5,6, 7-hexahydroindacen-4-yl) urea; or a pharmaceutically acceptable salt of same. 3. A pharmaceutical composition comprising a compound of claim 1 or claim 2, or a salt pharmaceutically acceptable thereof, and a vehicle pharmaceutically acceptable. 4. Use of a compound of claim 1 or claim 2, or a pharmaceutically acceptable salt of the same, in the manufacture of a medicine to treat a condition selected from the group consisting of meningitis and salpingitis, septic shock, disseminated intravascular coagulation and / or syndrome respiratory distress in adults, acute inflammation or chronic, arthritis, cholarigitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury, vasculitis, hypersensitivity acute and delayed graft rejection and graft disease in front of the host, autoimmune diseases including diabetes Type 1 mellitus and multiple sclerosis, diseases periodontals, interstitial pulmonary fibrosis, cirrhosis, sclerosis systemic, keloid formation, tumors that produce IL-1 as an autocrine growth factor, cachexia, Alzheimer's disease, percussion injury, depression, atherosclerosis and osteoporosis.